Neuropathic pain is defined as a complex, chronic pain that originates from pathology in the nervous system. This chronic pain is associated with a sensitization of sensory neurons, whereby they become hyperexcitable, giving rise to ectopic, spontaneous action potentials. Changes in expression or functional properties of voltage-gated sodium channels (VGSCs), which are essential to generation and propagation of action potentials in neurons, likely contribute to this hyperexcitability. Tetrodotoxin-sensitive (TTX-S) VGSCs have the ability to influence the excitable properties of neurons through subthreshold currents. Resurgent sodium currents (I-NaR) are an example of a subthreshold current which has been shown to be crucial to spontaneous firing in neurons, and may contribute to ectopic, high frequency burst discharge of action potentials that may cause chronic pain. I-NaR are unusual currents that are active during repolarization of the membrane potential. I-NaR is thought to arise from an atypical inactivation mechanism that allows channels to dwell transiently in an open configuration as they recover to a closed state. This unique recovery is proposed to result from open-channel block by an intracellular particle that binds to the sodium channel open state preventing the channel from inactivating by its classical mechanism. Evidence suggests the Nav 1.6 VGSC likely mediates this current with the C-terminus of the auxiliary ?4-subunit serving as the open- channel blocker. Although initially described in cerebellar Purkinje neurons, we report the presence of I-NaR in rat large and small dorsal root ganglion (DRG) neurons. While it is clear I-NaR could impact excitability in sensory neurons, basic knowledge of the fundamental properties of this unique current is deficient. As such, the goal of this proposal is to identify the specific molecular components which are involved in the electrogenesis of I-NaR in sensory neurons. Specifically, we ask (1) which TTX-S VGSC produces I-NaR in sensory neurons, (2) if the VGSC auxiliary ?4-subunit -subunit is necessary for I-NaR generation in sensory neurons, and (3) if expression of the ?4-subunit is altered following peripheral nerve injury. We hypothesize the Nav1.6 channel produces I-NaR in sensory neurons, the auxiliary ?4-subunit is necessary to produce I-NaR, and the expression of the ?4-subunit is altered following peripheral axotomy. To test these hypotheses we will use whole-cell voltage-clamp electrophysiology, VGSC isoform specific pharmacological inhibitors, single-cell RT-PCR, specific siRNAs targeted at the ?4-subunit, and real-time RT-PCR. The results from this research will determine which VGSC and associated proteins participate in the electrogensis of I-NaR in sensory neurons, and may determine if I-NaR contributes to the increased excitability following peripheral nerve injury.